Accepted Manuscript

Title: Exercise training and music therapy in elderly with

depressive syndrome: a pilot study

Author: W. Verrusio P. Andreozzi B. Marigliano A. Renzi V.

Gianturco MT. Pecci E. Ettorre M. Cacciafesta N. Gueli

PII: S0965-2299(14)00097-1
DOI: http://dx.doi.org/doi:10.1016/j.ctim.2014.05.012
Reference: YCTIM 1350

To appear in: Complementary Therapies in Medicine

Received date: 13-11-2012

Revised date: 27-5-2014
Accepted date: 28-5-2014

Please cite this article as: Verrusio W, Andreozzi P, Marigliano B, Renzi A, Gianturco
V, Pecci MT, Ettorre E, Cacciafesta M, Gueli N, Exercise training and music therapy in
elderly with depressive syndrome: a pilot study., Complementary Therapies in Medicine
(2014), http://dx.doi.org/10.1016/j.ctim.2014.05.012

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*Highlights (for review)

Highlights:

 Studies show that drugs are mostly ineffective in light/moderate depression

 Physical training and music may play a role in the treatment of depression
 Our results show that exercise and music may help control mood disturbances
 The improvement in mood seems to persist over time
 Further investigation of possible biological action mechanisms is needed

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Exercise training and music therapy in elderly with depressive
syndrome: a pilot study.

W. Verrusio1, P. Andreozzi1, B. Marigliano2, A. Renzi3, V. Gianturco1, MT. Pecci4, E.

Ettorre1, M. Cacciafesta1, N. Gueli1.

1
Department of Cardiovascular, Respiratory, Nephrological , and Geriatric Sciences,

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Sapienza University of Rome, Rome, Italy
2
Internal Medicine, Campus Bio-medico of Rome, Rome, Italy

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3
Department of Dynamic and Clinical Psychology, "Sapienza"- University of Rome
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“Science of Aging” Interdepartmental Research Center - Sapienza University of Rome

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Corresponding author:
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Dr. Walter Verrusio
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Specialist Geriatrician, PhD st.
Department of Cardiovascular, Respiratory, Nephrological , and Geriatric Sciences,
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Sapienza University of Rome

Viale del Policlinico 155, 00161 Roma, Italy
e-mail: walter.verrusio@uniroma1.it
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Abstract
Objective: Recent studies have thrown doubt on the true effectiveness of anti-depressants in
light and moderate depression. The aim of this study is to evaluate the impact of physical
training and music therapy on a sample group of subjects affected by light to moderate
depression versus subjects treated with pharmacological therapy only. Design and setting:
Randomized controlled study. Patients were randomized into two groups. Subjects in the
pharmacotherapy group received a therapy with antidepressant drugs; the exercise/music

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therapy group was assigned to receive physical exercise training combined with listening to
music. The effects of interventions were assessed by differences in changes in mood state

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between the two groups. Main outcome measures: Medically eligible patients were screened
with the Hamilton Anxiety Scale and with the Geriatric Depression Scale. We used plasmatic

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cytokine dosage as a stress marker. Results: We recruited 24 subjects (mean age: 75.5 ± 7.4,
11 M/13 F). In the pharmacotherapy group there was a significant improvement in anxiety
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only (p < 0.05) at 6-months. In the exercise/music therapy was a reduction in anxiety and in
depression at 3-months and at 6-months (p < 0.05). We noted an average reduction of the
level of TNF-a from 57.67 (± 39.37) pg/ml to 35.80 (± 26.18) pg/ml. Conclusions: Our
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training may potentially play a role in the treatment of subjects with mild to moderate
depression. Further research should be carried out to obtain more evidence on effects of
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physical training and music therapy in depressed subjects.

Keywords: anxiety; depression; exercise; music therapy; elderly; rehabilitation.

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INTRODUCTION
Depression and anxiety are frequent disorders in the elderly. Beyond the age of 65, the risk of
falling ill with depression increases threefold compared to the general population [1]. The
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Food and Drug Administration (FDA) recently released the data underlying the approval of
six of the most widely sold anti-depressants: in 47 controlled clinical studies, only 10-20%
showed benefits effectively attributable to the pharmacological action of the molecule
employed, while the placebo effect was responsible for the improved mood of 80-90% of the
subjects [2]. In confirmation of this finding, a recent study showed that drugs against
depression proved partially effective only in subjects suffering from severe depression [3]. In
recent years, therefore, extensive scientific evidence has thrown doubt on the true
effectiveness of anti-depressants, especially for patients affected by light or moderate

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depression. And we need, especially in the field of geriatrics, to look for new tools for the
treatment of mood disturbances.
Experience has been gained, over the last few years, with cognitive therapy (CT). A study
carried out on 240 patients suffering from moderate to severe depression showed that,
although the percentage of response to treatment with CT overlapped, to a certain extent, with
the response to pharmaceuticals, the long-term incidence of new episodes of depression in the
group treated with Selective serotonin reuptake inhibitors (SSRIs) was 54%, compared to

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17% among patients treated with CT [4]. This suggests not only that the effect of CT lasts
longer than that of pharmaceuticals, but that CT can produce changes which differ from those

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brought about by pharmaceutical therapy, making it a valid alternative to the use of anti-
depressants. In the field of geriatrics, other works have highlighted the positive effect of

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music on treating cognitive disturbances [5] and behavioural and psychological symptoms of
dementia (BPSD) [6] and on a whole series of unfavourable stress-induced circumstances,
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including anxiety and depression [7]. Recent research efforts examining the effects of
listening to music on the brain have discovered that music is able to increase cerebral synaptic
plasticity [8]. In other words, though they act through different mechanisms and have
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different effects, both depression and music work in a shared substrate of certain areas of the
brain, giving rise to a series of changes [9]. The fact is that exposure to sound leads to
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increased neurogenesis at the hippocampus, where neuron impoverishment due to loss and/or
scarce regeneration is thought to be an underlying cause of a variety of mood disturbances,
including depression [10]. Therefore there is a very close link between depression and music.
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Another therapeutic strategy recently proposed for the treatment of depressed subjects is
physical activity. Physical training helps control mood disturbances, especially those of light
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to moderate intensity, with a level of effectiveness comparable to that of psychological or

pharmacological therapies, especially over the long term [11] .
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In the present study, we used plasmatic cytokine dosage as a stress marker. Recent research
has pointed to an active role on the part of pro-inflammatory cytokines in the regulation of
synaptic plasticity, demonstrating that hyper-activation of the immune system can be
identified as part of the pathogenesis of depression [12]. Patients suffering from mood
disturbances have been found to present increases in Interleukin 1 (IL1), Interleukin 6 (IL6)
and Tumor Necrosis Factor alpha (TNFα), tied to a greater risk of cognitive disturbances and
mood depression, plus a reduced response to therapy [13]. The cytokine dosage, therefore,
can be used as a parameter for evaluating the effectiveness of a proposed therapy.

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The primary aim of this study is to determine whether exposure to music and physical training
can have a positive effect on the mood of elderly subjects suffering from light to moderate
depression, and whether the improvement in mood persists over time.
A secondary aim of the study is to evaluate the effective influence of aerobic physical training
on the concurrent disturbances of the subjects examined.

MATERIALS AND METHODS

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This was a randomized controlled trial . This study included a series of elderly subjects (n =
24; mean age: 75.5 ±7.4; 13 females) diagnosed according to the DSM-IV criteria with major

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depression with mild to moderate severity [14-15]. Each participant received information
about this study in writing and an individual verbal explanation of this study from the

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researcher. Participation was entirely voluntary. Individual participants in this study gave
written informed consent and a signed declaration of consent. This study was conducted
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according to the principles expressed in the Declaration of Helsinki and was approved by the
―Science of Aging‖ Interdepartmental Research Center of Sapienza University of Rome. We
evaluated the concurrent conditions through the Cumulative Illness Rating Score (CIRS) and
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its Comorbidity Index (CInd) [16]. The main diseases found in the test group were:
hypertension, obesity, diabetes mellitus, carbohydrate intolerance, dyslipidemia. Consistency
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with the following criteria of inclusion was assessed for each patient: diagnosis of light to
moderate depression, with a Geriatric Depression Scale (GDS) score between 5 and 12;
absence of pharmacological treatment. Patients suffering from severe depression, or for whom
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physical exercise was not recommended (blood pressure –SBP- >200 mmHg and/or diastolic
blood pressure –DBP- >110 mmHg; diabetic subjects with fasting blood glucose –FBG- >
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250 mg/dl; unstable angina pectoris; arrhythmias; severe heart valves diseases; aneurysms;
any kind of severe systemic diseases), were excluded.
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Participants were randomly assigned to the pharmacotherapy group or the exercise/music

therapy group using computerized random numbers. Group allocation was not communicated
to the patients until the first exercise/music session or the first prescription of the drug.
An electronic chart was filled out for each subject, recording the following parameters at the
start of the study (W0), at the three-month point (W12), after six months (W24) and, finally,
in the exercise/music therapy group at one month after the end of the study (W28):
- pharmacotherapy group: GDS for assessing mood; Hamilton Anxiety Scale (HAS) score for
evaluating anxiety;

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- exercise/music therapy group: GDS and HAS; standard laboratory techniques were used to
determine, after an overnight fast, plasma total cholesterol (TC), high-density lipoprotein
cholesterol (HDLc), triglycerides (TG), FBG and plasmatic cytokine dosage (TNFα, IL1,
IL6). Waist circumference (WC) was measured at the level of iliac crest with the patients
standing. The body mass index (BMI) was determined by dividing the weight (kilograms) by
the square of height (meters).
The pharmacotherapy group subjects were assigned to receive a antidepressant medication

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involving an SSRI in 9 patients (paroxetine 20 mg/die) and a specific serotonergic
antidepressant (NaSSA) in 2 patients (mirtazapine 30 mg/die), associated with

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benzodiazepine (Alprazolam) as needed.
The exercise/music therapy group subjects were assigned to receive physical exercise training

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combined with listening to music. Each patient engaged in two sessions of physical exercise a
week, with each session lasting approximately an hour. The routine consisted in: warm-up of
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muscles, general gymnastics or postural gymnastics, aerobic training on stationary bicycles or
treadmills, post-workout decompression. The physical activity was moderately intense so as
not to exceed the target pulse rate, meaning 75% of the maximum pulse rate for the patient
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being treated (based on the theoretical maximum pulse rate by age, or on the Borg scale) [17].
Blood pressure, resting heart rate, pulsoximetry and FBG were assessed before and after
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exercise. While the patients exercised, a collection of musical pieces was played. Three
different play-lists were used for the study, with the style of music selected in accordance
with the tastes of the patients, who were interviewed during the recruitment phase. Three
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different genres were identified: Jazz (Mt.1), Classical (Mt.2), Modern (Mt.3). The sample
group being examined was divided into 3 subgroups of four patients each, one for each play-
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list. The different songs on the various play-lists each corresponded to a specific phase of the
physical training session; each session was divided as follows:
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 warm up (light exertion, slow rhythm),

 main part (moderate-intense exertion, fast rhythm),
 cool down (decompression phase, slow rhythm).
For the portion of the study involving depression, the variations in mood were measured with
the GDS, a brief depression screening inventory composed of 15 items that require yes or no
answers. A score of 5 or more indicates depressed individuals [18]. The state of anxiety was
evaluated with the HAS. It consists of 14 items, each defined by a series of symptoms. Each
item is rated on a 5-point scale, ranging from 0 (not present) to 5 (severe). A score of 18 or
more indicates anxiety [19].

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An overall description was performed for each of the considered variables. For qualitative
variables, the frequencies of each modality were determined. For quantitative variables mean
and standard deviation were calculated. Mean values were compared using Student’s t-test.
The change in the parameters between groups was compared by one-way analysis of variance
and HAS score at baseline was used as covariate (ANCOVA), to control the effect of this
variable on outcome at 12 and 24 months (since it appeared marginally different in the two
groups). A 95% confidence intervals (CI) was calculated. A p value below 0.05 was deemed

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significant.

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RESULTS
24 patients were randomized into two groups: 12 subjects into the pharmacotherapy group

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(mean age: 76.1 ±7.1; CInd: 2.4 ±2.3; males/females: 4/8) and 12 subjects into the
exercise/music therapy group (mean age: 74.8 ±8; CInd: 2.1 ±0.7; males/females: 7/5) (Figure
1).
All patients completed the study protocol.
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The characteristics of the patients including age, Comorbidity Index, GDS and HAS scores
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were not significantly different between the two groups at baseline.
Table I shows test scores in the two groups.
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In the pharmacotherapy group there were minimal variations in GDS and HAS scores,
however there was a significant within group change in anxiety observed after 24 weeks
compared to baseline data (p < 0.05) (Figure 2). At 3-months, we prescribed in association
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therapy benzodiazepine (Alprazolam) to 6 patients and we increased antidepressant dosage in

4 patients (paroxetine, from 20 mg/ die to 40 mg/die). We also changed antidepressant
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therapy of 9 patients at 6-months because of side effects.

In the exercise/music group there were significant within group reductions both in anxiety and
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in depression observed after 12 and 24 weeks compared to baseline data (p < 0.05) (Figure 2).
In general, the physical training in our study was well tolerated and the exercise/music group
did not take any antidepressant medication during study period.
There were significant differences between the pharmacotherapy group and exercise/music
group for HAS measurements at week 12 and at week 24 and for GDS at week 24 (p < 0.05),
although the covariate for HAS at baseline was included (Table I).
The cytokine dosages in the serum of the exercise/music therapy group subjects examined
pointed to a linear correlation between high levels of cytokine and a high GDS score. In fact,
of the 12 patients examined, 9 presented a average GDS score of 7.44 (± 1.23) and

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undetectable doses of cytokines in the blood plasma, while 3 subjects showed a average GDS
score of 11.66 (± 0.57) combined with high levels of TNF-α. The following dosage reading,
taken at 24 weeks, showed that the average level of TNF-α in the three most depressed
subjects had fallen from 57.67 (± 39.37) pg/ml to 35.80 (± 26.18) pg/ml.
A new assessment of mood carried out 4 weeks (W28) after the suspension of the
rehabilitation program resulted in only minimal differences in the GDS and HAS scores. For
these parameters, the difference between W24 and W28 was minimal (GDS: -0.17 ± 0.58;

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HAS: 0.17 ± 1.03).
As for the secondary aim of the study, after 6 months we observed the following in the

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exercise/music therapy group: a reduction of 7 mmHg in the average systolic blood pressure
(p < 0.05) and 3 mmHg in the average diastolic blood pressure of the group examined; a

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variation in the lipid level, with average reductions of 27 mg/dl in TC (p < 0.05) and of 14.75
mg/dl in the TG; a reduction of 16.7 mg/dl in the levels of basic FBG (p < 0.05); an average
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reduction of 6.2 cm in the WC of the sample group examined (Table II).

DISCUSSION
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The primary aim of this study is to determine whether exposure to music and physical training
can have a positive effect on the mood of elderly subjects suffering from light to moderate
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depression and whether the improvement in mood persists over time. The results at the third
and sixth month show a two-fold positive effect in the exercise/music therapy group, reducing
both depression and the symptoms of anxiety in the group. We also observed progressive
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improvement linked to an increase in the number of sessions, pointing to the possibility of a

dose-dependent effect. On the contrary, in the pharmacotherapy group we observed only
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minimal variations in GDS and HAS scores at the third month and we observed a significant
reduction in anxiety only at 6-months.
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We assessed whether the positive results of our training lasted over time, subjecting the
subjects of the exercise/music therapy group to a new control 4 weeks after suspension of the
rehabilitation program. The results for both depression and anxiety showed only minimal
differences in the GDS and HAS scores. With regard to physical training, our study shows
that it has both a beneficial effect on mood and a positive influence on an entire series of
conditions that present a high rate of morbidity in the geriatric age bracket.
In light of these results, we hold that physical training associated with exposure to music is
capable of setting off a series of positive effects leading to modifications in both the
depressive and anxious components of the mood [20].

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Nevertheless the current study faces certain limitations. Firstly, the small size of the sample.
Other studies have analyzed the effect of music exposure or exercise training on depression
[21-23], but our study provides preliminary evidence of the combined benefit of exercise and
listening to music for mood disturbances in elderly patients. For this reason we have chosen
to study two groups of patients, a pharmacotherapy group versus an exercise/music therapy
group, exploring directly synergistic therapy. However, when analysing our results it is not
possible to disentangle the contribution of each component to the overall effect. Secondly,

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although the very small number of test subjects means that the result cannot be considered
statistically significant, the variations in cytokines levels of our study are similar to findings

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reported in other studies that have pointed to a correlation between high levels of cytokines
and depression [24]. These preliminary results seem to confirm that the cytokine dosages in

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the serum may potentially play a role as indicator of effectiveness for evaluating the
effectiveness of a antidepressive therapy but further studies are needed to better characterize
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these correlations. Thirdly, the results of our training in the exercise/music therapy group,
especially over the short term, can be attributed in part to the placebo effect, which,
nevertheless, can be used to good advantage when treating depressed subjects, especially in
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the early phases of a rehabilitation program. For the placebo effect can encourage the
depressed subject to take a more active role in the healing process while helping to create a
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good physician-patient relationship, in this way creating ideal conditions for pursuing the
therapeutic strategy over the long term, at which point the results will be influenced to a lesser
extent by the placebo effect.
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We feel that, despite the limitations of this pilot study, the results can have interesting
implications for clinicians in the management of light and moderate depression. It is known
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that modifications in the neuro-transmission of elderly subjects render them more vulnerable
to the extra-pyramidal and anticholinergic effects of anti-depressant pharmaceuticals,
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resulting in the frequent onset of side effects [1]. This also delays the construction of a
physician-patient relationship that is important for the management of depressed patients and
requires more time in order to find an effective therapy that is well tolerated by the patient. .
On the contrary, a variety of different mechanisms can be identified to explain the positive
effect of physical exercise on depression: the fact that the depressed subjects are taking care
of themselves heightens their self-reliance and esteem; the exercise leads to patients to have
more positive thoughts and plans; the alliance established between the patient and the care-
giver in ―taking action‖ to cure the depression and anxiety. Moreover, the results of the
present study demonstrate the positive effect of our training on all the risk factors linked to

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the metabolic syndrome. It is safe to say, that, even in terms of its ―side effects‖, our
rehabilitation program proved to be safe and effective (Table II). Unlike other studies [25-
26], the distinguishing feature of our study is the use of the style of music selected in
accordance with the tastes of the patients and the results show that our training had a
beneficial effect, albeit at varying levels, in each of the groups of patients that listened to the
different styles of music. Other original element of our study is the way it has combined two
such different techniques, namely physical exercise and music therapy. We have divided the

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training session in 3 phases (warm up, main part, cool down) in order to create close
association between musical rhythm and intensity of the activity being performed, in order to

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increase the synergistic effect of physical exercise associated with music therapy.
Future studies should be randomized controlled trials of exercise training and music therapy

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in depressed patients, including a systematic investigation of possible biological action
mechanism (e.g., reduction in inflammatory biomarkers) .

CONCLUSIONS
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The preliminary results allow us to state that:
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 Our training may potentially play a role in the treatment of subjects with mild to
moderate depression.
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 It appears that the improvement in mood may persist over short term: at a distance of
4 weeks from the suspension of our program, we observed that the benefits obtained
were essentially stable. In other words, our training may serve as a tool in the
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rehabilitation of mood disturbances.

 Thanks to the multidimensional approach of our program, we can treat both mood
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disturbances and the various comorbid conditions that can aggravate the psycho-
physical health of elderly patients.
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Further research should be carried out using a larger group of patients to obtain more
evidence on effects of physical training and music therapy in rehabilitation of subjects
affected by light to moderate depression.

Conflict of interest statement

The Authors declare that they have no competing financial interests.

References

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TITLES OF TABLES
Table I. Anxiety (HAS) and depression (GDS) in the two groups. Values at baseline (W0), 12

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weeks later (W12), 24 weeks later (W24) and differences between groups not-adjusted and

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adjusted for HAS score at baseline.

p < 0.05 = significant.

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Table II. Side effects of antidepressant medications and secondary effects of our training in
exercise/music therapy group.

FIGURE KEY
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Figure 1 The study flow chart.
Figure 2 Change in depression and anxiety scores. Means and standard deviation (error bars).
(GDS= Geriatric Depression Scale; HAS= Hamilton Anxiety Scale) *Significant difference
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between the two groups.

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Figure

Fig. 1 The study flow chart.

Assessed for eligibility (n=24)

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Excluded (n=0)
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ll participants assessed for eligibility met the
inclusion criteria

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Randomized (n=24)

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Allocated to Pharmacotherapy group (n=12) Allocated to Exercise/music therapy group
Received allocated intervention (n=12) (n=12)
Received allocated intervention (n=12)
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Lost to follow-up (n=0) Lost to follow-up (n=0)

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Continued follow up (n=12) Continued follow up (n=12)

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Analysed (n=12) Analysed (n=12)

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Figure 2

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Table 1

Table I Anxiety (HAS) and depression (GDS) in the two groups. Values at baseline (W0), 12

weeks later (W12), 24 weeks later (W24) and differences between groups not-adjusted and adjusted

for HAS score at baseline.

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Pharmacotherapy Exercise/music Differences between F; p F; p

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group therapy group groups Not-adjusted Adjusted

HAS Mean (SD) Mean (SD) [95% CI] F p F p

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W0 24,2 (± 5,3) 22,2 (± 5,07) -2.08 [-6.51 to 2.34] 0.95 .34 / /
W12 23,5 (± 3,5) 19,6 (± 4,8) -3.92 [-7.50 to -0.33] 5.14 .03 4.55 .04
W24 22 (± 4,7) 16,5 (± 2,7) -5.50 [-8.80 to -2.20] 11.92 .00 13.33 .00

GDS Mean (SD) Mean (SD) [95% CI] F p F p

W0
W12
W24
8,4 (± 1,8)
8,6 (± 2,9)
8 (± 2,5)
8,5 (± 2,2)
7,6 (± 1,6)
5,5 (± 1)
an
0.09 [-1.97 to 2.14]
-1.2 [-2.84 to 0.84]
-2.92 [-4.39 to -0.61]
0.01
1.08
10.44
.92
.31
.01
/
1.74
8.72
/
.20
.01
M
p< .05 = significant
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Page 16 of 18
Table 2

Table II Side effects of antidepressant medications and secondary effects of our rehabilitation

program

t
ip
ANTIDEPRESSANT DRUGS TRAINING

(value W24)

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MAOIs Hypertensive crisis, flushing,

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nausea

Constipation, weight gain,  reduction of 7 mmHg in the average

systolic pressure and 3,2 mmHg in
TCAs sexual dysfunction, dizziness,

memory disturbances, sedation

an the average diastolic pressure;

 average reductions of 15 % in total

SSRIs Dyspepsia, nausea, sexual cholesterol and of 10 % in the
M
triglycerides;
dysfunction
 reduction of 15 % in the levels of
NASSAs Weight gain, drowsiness, basic glycaemia;
ed

dizziness, headache
 average reduction of 6.2 cm in the
NARI Hypotension and tachycardia, waist measurements
pt

insomnia, urinary retention

NSRIs Dyspepsia, nausea, constipation

ce

Legend: MAOI = Monoamine oxidase inhibitors; TCA = Tricyclic antidepressants; SSRIs = Selective
Ac

serotonin reuptake inhibitors; NASSAs = Noradrenergic and specific serotonergic antidepressants; NARI =

selective noradrenaline reuptake inhibitor; NSRIs = Norepinephrine Serotonin Reuptake Inhibitors

Page 17 of 18
*Conflict of Interest statement

Rome 20/04/2013

Gentle Editors,

we submit for consideration of pubblication on Complementary Therapies in Medicine the

article intitled “Exercise training and music therapy in elderly with depressive syndrome: a

t
pilot study”.

ip
All the authors have not financial interests and conflicts of interest to declare.

cr
Best Regards

us
Dr. Walter Verrusio

an
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Page 18 of 18